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Overview on Epigenetics and Cancer

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Review Article | DOI: https://doi.org/10.31579/2690-8794/015

Overview on Epigenetics and Cancer

  • Eman Refaat Youness 1*
  • 1* Department of Medical Biochemistry, National Research Centre, Egypt

*Corresponding Author: Eman Refaat Youness, Department of Medical Biochemistry, National Research Centre, Egypt

Citation: Eman R Youness (2020) Overview on Epigenetics and Cancer,2(3): DOI: 10.31579/2690-8794/015

Copyright: © 2020 Eman Refaat Youness, This is an open-access article distributed under the terms of The Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Received: 19 February 2020 | Accepted: 27 February 2020 | Published: 09 March 2020

Keywords: epigenetics,chemical processes,cancer

Abstract

Epigenetics is considered as the science of hereditary phenotype which does not encompass amendment in the DNA. This occurs through chemical processes that modify the phenotype, without altering the genotype. A large number of studies showed that metabolic diseases are highly associated with epigenetic alterations suggesting that epigenetic factors may play a central role in cancer. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs, specifically microRNA expression. Studies of the mechanism(s) of epigenetic regulation and its reversibility have resulted in the identification of novel targets that may be useful in developing new strategies for the prevention and treatment of cancer.

Introduction

Epigenetics is considered as the science of hereditary phenotype which do not encompass amendment in the DNA [15]. This occurs through chemical processes that modify the phenotype, without altering the genotype[18]. In epigenetics, the Greek acanthus epi-(over) behold countenance which is "on the top of" i.e "in addition to" the conventional basis of inheritance of genetic [49]. Epigenetics frequently betoken changes that affect gene expression and activity. Also, it is used to depict each change in the heritable phenotype. Any effect in the physiological & cellular phenotypic traits could arise by environmental and external factors [6].

This means pertinent changes to the genome but not involve an alteration in the sequence of nucleotide. Expression of genes could be well-ordered via the repressor proteinswhich bind to silence regions in DNA. These alterations possibly will remain over cell divisionsfor the period of the cell's life. It could also continue in multiple generations while they include no variations in the sequence of DNA of the organism [7].

Figure (1): Different Kink in the Tail but Same Genes

Epigenetic alterations amend definite genes activation, not the genetic code DNA sequence. The structure of DNA or the related chromatin proteins may be adjusted, producing either silencing or activation. This mechanization allows cells to make the genes that are essential for their own activity only. Epigenetic alterations conserved during cell division. The majority of epigenetic alterations occur only within lifetime of the organism. These alterations could be patrimonial to progeny via a process termed trans-generational epigenetic inheritance. Additionally, whether gene inactivation occurs in an egg or sperm which leads to fertilization, this epigenetic modification could be transmitted to the following offspring [8].

Epigenetic Phenomena

Epigenetics and development continue from solitary impregnated embryo into immeasurable various tissues and cells [39]. It was notable that more modern and accurate epigenetic concept could be observed early in variegating eye colour in Drosophila which changes from generation to another [29]. In yeast, the effect of telomere location found like the idea of semen as it switches among phenotypes happens with no genotypic variation [19]. Epigenetics still in its infancy, by the persistent appearance of new states (bivalent promoters), novel players (lncRNAs) and novel histonemodification [39].

DNA is compacted in chromatin and nucleosome is its basic unit. Each nucleosome is formed of histone. This histone surrounded by about 145–147 DNA base pairing. Histone designed as four proteins couples, named H2A, H2B, H3, and H4. DNA is firstly “supercoiled” and then wrapped onto histones, to allow their compressing into a single cell [33].There are two types of chromatins rendering to the grade of winding of DNA. DNA in euchromatin, is extra relaxed allowing genes transcription, & DNA in heterochromatin is super-coiled and cannot accessed for gene transcription (Figure.2).

Figure (2): Chromatin structure representation, including DNA and histones, which become ready for epigenetic marks.

There is equilibrium between euchromatin & heterochromatin that authorize the cells to amend gene expression. This leads to notable alterations in their biological and functions phenotypes[58]. This merit achieves from the same DNA sequence; cells might discriminate in actual dissimilar means. The renovation between euchromatin and heterochromatin is called epigenetic regulation[43].Sequence; cells might discriminate in actual dissimilar means. The renovation between euchromatin and heterochromatin is called epigenetic regulation [43].

The Major Epigenetic Mechanisms

DNA methylation

Methylation of DNA is firmly concomitant with parental imprinting, circumstantial regulation of gene expression and time, silencing of repetitive elements, inactivation of X-chromosome, human diseasesand cell differentiation (Tirado-Magallanes et al., 2017). Chemical process in the methylation of DNA, a CH3 group is linked together with cytosine residue at C5, producing 5-methylcytosine (5mC) (Figure 3).

Figure (3): DNA methylation

Methylation of DNA is implement by DNA methyltranferase (DNMTs) certain sequences in DNA specially rich in guanine & cytosine nucleotide pairs, termed CpG areas, are the idealgoal of DNMTs. CpG regions in DNA of humans, (5'—C—phosphate—G—3') are not distributed at random. They are focused in small enriched CpG DNA morsels, termed CpG islands. Around 60% of all promoters in genes are wealthy of CpG islands, so these genes can be regulated epigenetically. There are 2 types of DNMT. DNMT1, which conserves predating manner of methylation next DNA replication in the cells, DNMT3A & DNMT3B, called “de novo” DNMT, that methylate earlier unmethylated DNA [43].

Demethylation of DNA could be passive, a method emerging due to DNA replication deprived of de novo methylation coupling, or active; this including the interposes 5-formylcytosine (5fC), 5-hydroxymethylcytosine (5hmC), also, 5-carboxycytosine (5caC) [47]. The active demethylation be contingent on protein complexes (demethylase) as base-excision repair (BER) and thymine DNA glycosylase (TDG) [26].

General patterns for DNA methylation that manipulate the gene expression regulation are abridged herein figure (4) [24].

Figure (4): Mechanisms of transcriptional regulation during promoter methylation of DNA. (A): a promoter that is transcriptionally active, (TFs) transcription factors cause open chromatin by means of relative nucleosome lessening & transcriptional (CoA)co-activator presence. The conclusion was reached during protein complexes by way of e.g. histone methylation (HM), histone acetylase (HAT), and histone demethylation (HDM) activities. (B):After methylation of promoter of DNA, binding of transcription factors is prohibited by plugged of the distinct recognition of sequences. This cause diminished activity of the promoter. (C): After DNA promoter methylation, 5mC induct methyl-CpG binding protein 2 (MeCP2) & members of the methyl-CpG binding  protein (MBP). These proteins are able toplay a role in mediating transcriptional repressionof protein complexes.This depends on histone HM, (HDAC) deacetylase, & HDM activities on the way to histone tail residues, and induct transcriptional co-repressors (CoR). (D): Chromatin remodeling and compaction leads to an oppressive transcriptional context.

Genes that transcribed actively are generally conspicuous hypo-methylation around the transcription start point. The intricacy of the link between methylation and DNA transcription was demonstrated through genes together with promoters possessing decreased content of CpG region and hypermethylation that transcriptionally active; e.g., in gamete formation [21]. Furthermore, genes that are transcriptionally active are usually hypermethylated in the gene of the body [4]. This is supposed to chunk the start of false transcription, promote production of abnormal RNAs [40].

Human being genome comprises about fifty six million sites for CpG, about 65–75% of them be methylated [28]. During genome, sites of CpG are distributed unequally. CpG islands are demarcated as zones with minimum size, 550 b.p [12]. During the mammalian life cycle, epigenetic marks endure wide reprogramming and methylation of the CpG site, both are developmentally planned and gained environmentally. They reprogrammed in general after fertilization throughout early gametogenesis and in the zygote proximately[55]. Reprogramming includes wiping off of most DNA methylation that followed by the formation of newgroups of marks of DNA methylation [37]. The wiping off of DNA methylation throughout reprogramming was wide-ranging however, some DNA methylation continues and smooth the way for potential epigenetic inheritance [59].

DNA Hydroxymethylation

Hydroxymethylation of Cytosine was concealed as another significant epigenetic modification of DNA in mammals. Like methylation, hydroxymethyl group replaces the hydrogen atom at the cytosine position-C5, (fig 5).

Figure (5): Comparison of cytosine, methylcytosine and hydroxymethylcytosine

It has been elucidated that hydroxymethylation of cytosine is involved also in gene regulation. e.g., the hydroxymethylation level was linked with the stem cells pluripotency. Disturbing of DNA cytosine hydroxymethylation could lead to jumbled cell functions; give rise to altered species of cancers, such as cancers of myeloid [45].

Histone and DNA

Proteins termed histones are that relate the DNA in chromosomes in eukaryotes forming basic units named nucleosomes. The DNA double helix is swathed around histones. Then these nucleosomes packed together to form chromatin. Chromatin appears as visible stainable mass under microscope during cell division. This chromatin comprises the chromosome bounded by non-histone and histone proteins [1](Fig 6).

Figure(6): Nucleosomes help package the DNA in a compact form that fits in the nucleus of the cell

In mammals, all chromatin structure can be inherited is a form of epigenetic inheritance since it does not require the direct modification of DNA. The highly condensed form of chromatin, heterochromatin, can switch off any genes in this way. This type of chromatin can be effective as an epigenetic mechanism, as the DNA is stiffer to access to be transcribed. In the other type of chromatin, euchromatin, there is an open chromatin and the genes are ready to be accessed. It was found that genes in heterochromatin are commonly silenced and active in euchromatin [36].

Just as DNA is methylated, histones may also be modified, by methylation, phosphorylation, acetylation, ADP ribosylation and proline isomerization, but these methods of histone modification have not all presented an obvious epigenetic effect similar to DNA methylation [52].

Histone modifications

Histone covalent modifications play an imperative role in epigenetic regulation.This occurs though binding of different enzymes to histones causing phosphorylation, acetylation, methylation, or ubiquitylation to them. These modulations result in gene transcription & chromatin relaxation. On the other side, chromatin compaction & gene repression occur. Whereas DNA methylation cause silence to histone modifications, gene expression, are capable for activation or silencing of genes. This depends on adding residues on the beleaguered histones, finally on the degree of the modulation [55]. E.g., lysine acetylation at the N-terminal of histone is capable to eradicate the histones positive charge, allowing negatively charged DNA to be detached from them and gaina transcription-ready arrangement. Furthermore, methylation of histonelysine leads to transcriptional activation or suppression. This depends on the position of methylated lysine. Acetylation of histones is interposed by(HAT) histone acetyltransferase, whereas deacetylations are encouraged by (HDAC) histone deacetylases. In acetylation and methylation, the preferred targets are the H3 and H4 center histones the same as the enormous preponderance of covalent modifications include them. In general, H4K20 methylation, H3K27 and histone H3K9 (lysine in position 9 ofthe H3 histone), are related with repression of gene. Conversely, methylation of H3K36 & H3K4, also, acetylation of H4 &H3, categorizes zones of active gene expression [33].

Regulation of miRNA

Mi- RNAs (mi-RNAs) are short non-coding RNAs (18–20 nucleotides), that join messenger RNA (mRNAs) through complete or incomplete matching their 3' untranslated zones and resulting in their deprivation and post-transcriptional gene silencing. Various mi-RNAs positions are situated in the intron regions. Mi-RNAs are capable to permit epigenetic control on apoptosis, and other fateful biological processes [14].

Abnormalities of epigenetic in tumorigenesis

Mechanisms of epigenetics are in demanded for preserving normal development, growth & expression of genes in various organs. Abnormality of epigenetic regulation may change the expression of genes and functions which could result in diseases as cancer. During formation of cancer, a large number of mutated genes are produced or abnormally activated [9].

There is equilibrium between euchromatin & heterochromatin that authorize the cells to amend gene expression. This leads to notable alterations in their biological and functions phenotypes [58]. This merit achieves from the same DNA sequence; cells might discriminate in actual dissimilar means. The renovation between euchromatin and heterochromatin is called epigenetic regulation (Perria et al. 2017).

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Hao Jiang

As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.

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Dr Shiming Tang

Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.

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Raed Mualem

International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.

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Andreas Filippaios

Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.

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Dr Suramya Dhamija

Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.

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Bruno Chauffert

I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!

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Baheci Selen

"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".

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Jesus Simal-Gandara

I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.

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Douglas Miyazaki

We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.

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Dr Griffith

I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.

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Dr Tong Ming Liu

I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.

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Husain Taha Radhi

I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.

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S Munshi

Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.

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Tania Munoz

“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.

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George Varvatsoulias

Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.

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Rui Tao

Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.

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Khurram Arshad